Due to the fact that the prevalence of microbial pathogens with resistance towards standard antibiotic therapy constantly increases, research has started to focus on the search and development of new antimicrobial drugs with novel modes of action. Natural products are traditionally a rich source of bioactive compounds, but although terpenoids are by far the largest class of natural products there are only three approved antimicrobial drugs in the terpenoid family and all three are semisynthetic derivatives of the fungal natural product pleuromutilin (tiamulin, valnemulin and retapamulin).
Basidiomycetes are a particularly rich source of complex, structurally diverse, and bioactive sesquiterpenoids, and certain protoilludene-type sesquiterpenoid aryl esters from the genus Armillaria are promising leads for the development of new antimicrobial drugs. The genus Armillaria, also commonly known as the honey mushroom, is currently classified in the family Physalacriaceae and comprises more than 600 species worldwide. Armillaria species are regarded not only as edible mushrooms, but also as notorious root pathogens attacking hardwood trees and conifers, as well as fruit trees and grapevine.
Member of the genus Armillaria are known for the production of two types of sesquiterpenoid protoilludene type aryl esters, which are divided according to the position of the double bond into armillylorsellinates and melleolides. Today more than 50 armillylorsellinate and melleolide structures are known from Armillaria spp., which makes them one of the most diverse groups of natural products known from fungi.
Whilst the biosynthesis of some terpenes, in particular of plants origin—like menthol, artemisinin or taxol—have been extensively studied in the past, little is known about the synthesis of the vast majority, in particular of terpenes produced by fungi.
Protoilludene type aryl esters are built from a sesquiterpenoid protoilludanol alcohol and orsellinic acid derived aromatic moiety. The biosynthesis of all melleolide and armillylorsellinate type sesquiterpenoids are thought to be derived from the cyclization of the universal sesquiterpene precursor farnesyl-diphosphate to protoilludene. The protoilludene ring system is then subject to several hydroxylation reactions, and the resulting protoilludanol alcohols are then subject to esterification at the C5-hydroxy position with polyketide orsellinic acid derivatives.
Whereas orsellinic acid and derivatives are biosynthesized by numerous microorganisms, and protoilludenes are widespread in homobasidiomycetes, the coupling of both seems to be unique to the genus Armillaria. 